Retinoids, both natural and synthetic, are derivatives of vitamin A. Retinoids have been recognized to induce a broad spectrum of biological effects. Thus, retinoid therapy ranges from therapeutic treatments for dermatological conditions, such as acne and psoriasis, to the treatment of metabolic disorders. In addition, RXR selective compounds are believed to be useful for the treatment and prevention of skin diseases, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses, keratinization and hyperproliferative skin disorders, eczema, atopic dermatitis, Darner's disease, lichen planus, steroid atrophy, topical microbial infections, skin photodamage, type II diabetes, eye disease, retinal detachment, dry eye, comeopathies, cardiovascular disease, dyslipidemias, post-angioplasty restenosis, HPV infections, genital warts, inflammatory disease, ileitis, colitis, Crohn's disease, neurodegeneration, Alzheimer's disease, Parkinson's disease, stroke, pituitary dysfunction, growth hormone deficiency, hair loss, organ rejection, immune disorders, wounds, as well as a variety of cancerous and pre-cancerous conditions, such as acute promyleocytic leukemia, cutaneous T-cell lymphoma, epithelial cancers, squamous cell carcinoma, and breast cancer, as well as in the treatment of hyperthyroidism, dyslipidemia, and hypertension. See, e.g, WO 9712853, WO 0026173, WO 9321146, WO 9504036, WO 0020397, WO 0020370, WO 9845242, EP 0790228, EP 0933350, WO 9908992, WO 9420093, WO 9417796, WO 9639374, EP 0933350, WO 9710819, WO 9963980, WO 9958487, WO 995848, WO 0001679 and Vuligonda et al., Bioorg. Med. Chem. Lett., 9:589–594 (1999).
Retinoids regulate the activity of two distinct nuclear receptor families, the retinoic acid receptors (“RAR”) and the retinoid X receptors (“RXR”). As with the RAR subfamily (currently including α, β, and γ isoforms), the RXR subfamily (currently including α, β, and γ isoforms) are recognized as ligand-induced transcription factors. Nevertheless, RARs and RXRs diverge in their primary structure and have only a 27% homology in the ligand binding domains. Thus, these structural differences provide for relative degrees of responsiveness among different retinoids. For example, certain retinoids have been identified that show selective binding to RXRs, but only a weak affinity for RARs. See, e.g., Lala et al., Nature, 83, 450–453 (1996). Furthermore, RARs and RXRs have distinct differences in their tissue distribution. RARs are expressed at high levels in visceral tissues, whereas RXRα is most abundant in the liver, kidney, lung, muscle, and intestine. Thus, while the subfamilies are related, each elicits distinct physiological responses apart from the other. Therefore, retinoids that are selective for either RARs or RXRs would provide for the independent control of the physiological responses mediated by the particular receptors. In addition, RXR dimerizes with many nuclear receptors (e.g., RAR, LXR, VDR, FXR, PPAR, and TR), as well as with itself to form a homodimer. Thus, retinoids that preferentially affect the RXR receptor, may additionally exhibit selectivity for specific heterodimer pairs as well.